HIV is recognized as a devastating infection that leads to severe morbidity and earlier death. It is known that HIV infection is associated not only with disruptions in immune function but also in sleep with daytime fatigue, somnolence and impaired quality of life. Highly Active Anti-Retroviral Therapy (HAART) is now extending the life expectancy of those infected with HIV either allowing or producing chronic medical conditions and significant associated medical comorbidity. Our preliminary data indicate that both HIV infection and HAART are associated with substantial daytime fatigue. Moreover, HAART is also associated with sleep apnea, a known cause of sleep disruption and daytime somnolence. Our major hypothesis is that HIV infection, HAART, and associated alterations in humoral factors and cellular immunity lead to sleep disruption and sleep apnea, which both cause daytime dysfunction. In Specific Aim 1, we will elucidate the effects of HIV and HAART on nocturnal sleep architecture and daytime function. We hypothesize that HIV infection will be associated with sleep disruption and alterations in measures of daytime sleepiness, neurocognitive and neurobehavioral function, and quality of life. In Specific Aim 2, we will delineate the effects of HIV and HAART on the severity of upper airway obstruction and sleep. We hypothesize that HAART, but not HIV infection, is associated with an increased susceptibility for sleep apnea due to alterations in regional fat distribution and leptin. In Specific Aim 3, we will elucidate specific humoral and molecular pathways involved in the pathogenesis of upper airway, ventilatory and sleep/wake dysregulation. In this proposal, we capitalize on the well-established Baltimore site or the Multicenter Aids Cohort Study (MACS), a longitudinal study of HIV infection in gay men, to determine the impact of these factors on sleep quality, sleep apnea and daytime function. In a series of complementary murine studies, we further probe causal pathways involved in the pathogenesis of upper airway, respiratory and sleep/wake dysfunction. Conventional methods will be employed to assess sleep architecture, cellular immunity, humoral factors and daytime function, while novel analytic approaches will be used to quantify effects of HIV infection and therapy on sleep structure and upper airway function.